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1.
J Clin Med ; 10(22)2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34830660

RESUMO

An important component of severe COVID-19 disease is virus-induced endothelilitis. This leads to disruption of normal endothelial function, initiating a state of failing normal clotting physiology. Massively increased levels of von Willebrand Factor (VWF) lead to overwhelming platelet activation, as well as activation of the enzymatic (intrinsic) clotting pathway. In addition, there is an impaired fibrinolysis, caused by, amongst others, increased levels of alpha-(2) antiplasmin. The end result is hypercoagulation (proven by thromboelastography® (TEG®)) and reduced fibrinolysis, inevitably leading to a difficult-to-overcome hypercoagulated physiological state. Platelets in circulation also plays a significant role in clot formation, but they themselves may also drive hypercoagulation when they are overactivated due to the interactions of their receptors with the endothelium, immune cells or circulating inflammatory molecules. From the literature it is clear that the role of platelets in severely ill COVID-19 patients has been markedly underestimated or even ignored. We here highlight the value of early management of severe COVID-19 coagulopathy as guided by TEG®, microclot and platelet mapping. We also argue that the failure of clinical trials, where the efficacy of prophylactic versus therapeutic clexane (low molecular weight heparin (LMWH)) were not always successful, which may be because the significant role of platelet activation was not taken into account during the planning of the trial. We conclude that, because of the overwhelming alteration of clotting, the outcome of any trial evaluating an any single anticoagulant, including thrombolytic, would be negative. Here we suggest the use of the degree of platelet dysfunction and presence of microclots in circulation, together with TEG®, might be used as a guideline for disease severity. A multi-pronged approach, guided by TEG® and platelet mapping, would be required to maintain normal clotting physiology in severe COVID-19 disease.

2.
Semin Thromb Hemost ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34624913

RESUMO

The functions of platelets are broad. Platelets function in hemostasis and thrombosis, inflammation and immune responses, vascular regulation, and host defense against invading pathogens, among others. These actions are achieved through the release of a wide set of coagulative, vascular, inflammatory, and other factors as well as diverse cell surface receptors involved in the same activities. As active participants in these physiological processes, platelets become involved in signaling pathways and pathological reactions that contribute to diseases that are defined by inflammation (including by pathogen-derived stimuli), vascular dysfunction, and coagulation. These diseases include Alzheimer's and Parkinson's disease, the two most common neurodegenerative diseases. Despite their unique pathological and clinical features, significant shared pathological processes exist between these two conditions, particularly relating to a central inflammatory mechanism involving both neuroinflammation and inflammation in the systemic environment, but also neurovascular dysfunction and coagulopathy, processes which also share initiation factors and receptors. This triad of dysfunction-(neuro)inflammation, neurovascular dysfunction, and hypercoagulation-illustrates the important roles platelets play in neuropathology. Although some mechanisms are understudied in Alzheimer's and Parkinson's disease, a strong case can be made for the relevance of platelets in neurodegeneration-related processes.

3.
Cardiovasc Diabetol ; 20(1): 172, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34425843

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by acute clinical pathologies, including various coagulopathies that may be accompanied by hypercoagulation and platelet hyperactivation. Recently, a new COVID-19 phenotype has been noted in patients after they have ostensibly recovered from acute COVID-19 symptoms. This new syndrome is commonly termed Long COVID/Post-Acute Sequelae of COVID-19 (PASC). Here we refer to it as Long COVID/PASC. Lingering symptoms persist for as much as 6 months (or longer) after acute infection, where COVID-19 survivors complain of recurring fatigue or muscle weakness, being out of breath, sleep difficulties, and anxiety or depression. Given that blood clots can block microcapillaries and thereby inhibit oxygen exchange, we here investigate if the lingering symptoms that individuals with Long COVID/PASC manifest might be due to the presence of persistent circulating plasma microclots that are resistant to fibrinolysis. METHODS: We use techniques including proteomics and fluorescence microscopy to study plasma samples from healthy individuals, individuals with Type 2 Diabetes Mellitus (T2DM), with acute COVID-19, and those with Long COVID/PASC symptoms. RESULTS: We show that plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits (microclots). We also show that these microclots in both acute COVID-19 and Long COVID/PASC plasma samples are resistant to fibrinolysis (compared to plasma from controls and T2DM), even after trypsinisation. After a second trypsinization, the persistent pellet deposits (microclots) were solubilized. We detected various inflammatory molecules that are substantially increased in both the supernatant and trapped in the solubilized pellet deposits of acute COVID-19 and Long COVID/PASC, versus the equivalent volume of fully digested fluid of the control samples and T2DM. Of particular interest was a substantial increase in α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits. CONCLUSIONS: Clotting pathologies in both acute COVID-19 infection and in Long COVID/PASC might benefit from following a regime of continued anticlotting therapy to support the fibrinolytic system function.


Assuntos
Antifibrinolíticos/metabolismo , Fatores de Coagulação Sanguínea/metabolismo , COVID-19/complicações , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/patogenicidade
4.
Exp Cell Res ; 406(1): 112759, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34332984

RESUMO

The Serum Amyloid A (SAA) family of proteins is associated with various pathological conditions, including cancer. However, their role in cancer is incompletely understood. Here, we investigated the role of SAA1 in cell cycle regulation, apoptosis, survival signaling, metabolism, and metastasis in models of triple-negative breast cancer (TNBC), using RNAi. Our data show that in untransformed epithelial cells (MCF12A), the knockdown of SAA1 induces the expression of cell cycle regulators (MCM2, p53), the activation of DNA repair (PARP synthesis), and survival signaling (NFκB). In contrast, knockdown of SAA1 in the TNBC cell line (MDA-MB-231) induced the expression p16 and shifted cells in the cell cycle from the S to G2/M phase, without the activation of DNA repair. Moreover, in SAA1-deficient MDA-MB-231 and HCC70 cells, metabolism (NADH oxidation) continually increased while cell migration (% wound closure and the rate of wound closure) decreased. However, silencing of SAA1 altered epithelial and mesenchymal markers in MCF12A (E-cadherin, Laminin 1ß, Vimentin) and MDA-MB-231 (α-Smooth muscle actin) cells, associated with the metastatic program of epithelial-mesenchymal transition. Nonetheless, our data provide evidence that SAA1 could potentially serve as a therapeutic target in TNBC.


Assuntos
Apoptose/genética , Ciclo Celular/genética , Movimento Celular/genética , Células Epiteliais/metabolismo , Proteína Amiloide A Sérica/genética , Actinas/genética , Actinas/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Laminina/genética , Laminina/metabolismo , Componente 2 do Complexo de Manutenção de Minicromossomo/genética , Componente 2 do Complexo de Manutenção de Minicromossomo/metabolismo , Modelos Biológicos , NF-kappa B/genética , NF-kappa B/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteína Amiloide A Sérica/antagonistas & inibidores , Proteína Amiloide A Sérica/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Vimentina/genética , Vimentina/metabolismo
5.
Front Immunol ; 12: 688861, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335591

RESUMO

Psoriasis (PsO) is a common T cell-mediated inflammatory disorder of the skin with an estimated prevalence of 2%. The condition manifests most commonly as erythematous plaques covered with scales. The aetiology of PsO is multifactorial and disease initiation involves interactions between environmental factors, susceptibility genes, and innate and adaptive immune responses. The underlying pathology is mainly driven by interleukin-17. In addition, various inflammatory mediators from specific T helper (TH) cell subsets, namely TH1, TH17, and TH22, are overexpressed in cutaneous lesions and may also be detected in the peripheral blood of psoriatic patients. Moreover, these individuals are also at greater risk, compared to the general population, of developing multiple comorbid conditions. Cardiovascular disease (CVD) has been recognised as a prominent comorbidity of PsO. A potential mechanism contributing to this association may be the presence of a hypercoagulable state in these individuals. Inflammation and coagulation are closely related. The presence of chronic, low-grade systemic inflammation may promote thrombosis - one of the major determinants of CVD. A pro-inflammatory milieu may induce the expression of tissue factor, augment platelet activity, and perturb the vascular endothelium. Altogether, these changes will result in a prothrombotic state. In this review, we describe the aetiology of PsO, as well as the pathophysiology of the condition. We also consider its relationship to CVD. Given the systemic inflammatory nature of PsO, we evaluate the potential contribution of prominent inflammatory mediators (implicated in PsO pathogenesis) to establishing a prothrombotic state in psoriatic patients.


Assuntos
Coagulação Sanguínea , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Psoríase/complicações , Pele/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Trombose/etiologia , Animais , Anti-Inflamatórios/uso terapêutico , Anticoagulantes/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/prevenção & controle , Fatores de Risco de Doenças Cardíacas , Humanos , Prognóstico , Psoríase/sangue , Psoríase/tratamento farmacológico , Psoríase/imunologia , Medição de Risco , Pele/efeitos dos fármacos , Pele/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Trombose/sangue , Trombose/tratamento farmacológico , Trombose/imunologia
6.
Biosci Rep ; 41(8)2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34328172

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One of the most important pathologies, is hypercoagulation and microclots in the lungs of patients. Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron and fluorescence microscopy as well as mass spectrometry, we investigate the potential of this inflammagen to interact with platelets and fibrin(ogen) directly to cause blood hypercoagulation. Using platelet-poor plasma (PPP), we show that spike protein may interfere with blood flow. Mass spectrometry also showed that when spike protein S1 is added to healthy PPP, it results in structural changes to ß and γ fibrin(ogen), complement 3, and prothrombin. These proteins were substantially resistant to trypsinization, in the presence of spike protein S1. Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.


Assuntos
COVID-19/patologia , Fibrina/metabolismo , Fibrinólise/fisiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Trombose/patologia , Adulto , Idoso , Amiloide/metabolismo , Plaquetas/metabolismo , Complemento C3/metabolismo , Feminino , Fibrinogênio/metabolismo , Humanos , Pulmão/patologia , Masculino , Técnicas Analíticas Microfluídicas , Pessoa de Meia-Idade , Protrombina/metabolismo , SARS-CoV-2/metabolismo , Trombose/virologia , Tripsina/metabolismo
7.
Sci Rep ; 11(1): 13043, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158537

RESUMO

Psoriasis is a chronic, immune-mediated inflammatory skin disease, affecting approximately 2% of the general population, which can be accompanied by psoriatic arthritis (PsA). The condition has been associated with an increased cardiovascular burden. Hypercoagulability is a potential underlying mechanism that may contribute to the increased risk of major cardiovascular events in psoriatic individuals. Whole blood samples were collected from 20 PsA patients and 20 healthy individuals. The concentrations of inflammatory molecules (C-reactive protein, serum amyloid A, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and soluble P-selectin) were determined by enzyme-linked immunosorbent assays. In addition, clotting efficiency was evaluated by thromboelastography. The fibrin network architecture was also assessed by scanning electron microscopy. Elevated levels of circulating inflammatory molecules were significantly associated with the presence of psoriatic disease. Furthermore, an increased tendency towards thrombus formation was significantly predictive of disease presence. Scanning electron microscopy revealed that fibrin clots were denser in psoriatic individuals, compared to healthy controls, with an increased fibrin fibre diameter associated with psoriatic disease. Our results add to the accumulating evidence of the systemic nature of psoriasis and the subsequent risk of cardiovascular comorbidities, potentially due to an acquired hypercoagulability. We suggest that haemostatic function should be monitored carefully in psoriatic patients that present with severe disease, due to the pre-eminent risk of developing thrombotic complications.


Assuntos
Células Endoteliais/patologia , Hemostáticos/metabolismo , Inflamação/complicações , Psoríase/complicações , Artrite Psoriásica/sangue , Artrite Psoriásica/diagnóstico , Estudos de Casos e Controles , Feminino , Fibrina/ultraestrutura , Humanos , Inflamação/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Psoríase/sangue , Tromboelastografia
8.
Front Immunol ; 12: 649465, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968041

RESUMO

The immune and inflammatory responses of platelets to human immunodeficiency virus 1 (HIV-1) and its envelope proteins are of great significance to both the treatment of the infection, and to the comorbidities related to systemic inflammation. Platelets can interact with the HIV-1 virus itself, or with viral membrane proteins, or with dysregulated inflammatory molecules in circulation, ensuing from HIV-1 infection. Platelets can facilitate the inhibition of HIV-1 infection via endogenously-produced inhibitors of HIV-1 replication, or the virus can temporarily hide from the immune system inside platelets, whereby platelets act as HIV-1 reservoirs. Platelets are therefore both guardians of the host defence system, and transient reservoirs of the virus. Such reservoirs may be of particular significance during combination antiretroviral therapy (cART) interruption, as it may drive viral persistence, and result in significant implications for treatment. Both HIV-1 envelope proteins and circulating inflammatory molecules can also initiate platelet complex formation with immune cells and erythrocytes. Complex formation cause platelet hypercoagulation and may lead to an increased thrombotic risk. Ultimately, HIV-1 infection can initiate platelet depletion and thrombocytopenia. Because of their relatively short lifespan, platelets are important signalling entities, and could be targeted more directly during HIV-1 infection and cART.


Assuntos
Plaquetas/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Trombocitopenia/imunologia , Trombose/imunologia , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , Plaquetas/efeitos dos fármacos , Plaquetas/virologia , Linfócitos T CD4-Positivos/imunologia , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/imunologia , Quimioterapia Combinada , Eritrócitos/imunologia , Infecções por HIV/sangue , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , HIV-1/metabolismo , Humanos , Agregação Plaquetária/imunologia , Trombocitopenia/sangue , Trombocitopenia/virologia , Trombose/sangue , Trombose/virologia , Carga Viral , Replicação Viral/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo
9.
TH Open ; 5(2): e155-e162, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34007954

RESUMO

Cerebral aneurysms are balloon-like structures that develop on weakened areas of cerebral artery walls, with a significant risk of rupture. Thrombi formation is closely associated with cerebral aneurysms and has been observed both before and after intervention, leading to a wide variability of outcomes in patients with the condition. The attempt to manage the outcomes has led to the development of various computational models of cerebral aneurysm thrombosis. In the current study, we developed a simplified thrombin-fibrinogen flow system, based on commercially available purified human-derived plasma proteins, which enables thrombus growth and tracking in an idealized cerebral aneurysm geometry. A three-dimensional printed geometry of an idealized cerebral aneurysm and parent vessel configuration was developed. An unexpected outcome was that this phantom-based flow model allowed us to track clot growth over a period of time, by using optical imaging to record the progression of the growing clot into the flow field. Image processing techniques were subsequently used to extract important quantitative metrics from the imaging dataset, such as end point intracranial thrombus volume. The model clearly demonstrates that clot formation, in cerebral aneurysms, is a complex interplay between mechanics and biochemistry. This system is beneficial for verifying computational models of cerebral aneurysm thrombosis, particularly those focusing on initial angiographic occlusion outcomes, and will also assist manufacturers in optimizing interventional device designs.

11.
Microsc Microanal ; 27(2): 425-436, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33526165

RESUMO

Breast cancer (BC) is one of the most prevalent forms of cancer in women worldwide. Clinical research indicates that BC patients are at an increased risk for thrombotic events, drastically decreasing their quality-of-life and treatment outcomes. There is ample evidence of this in the literature, but it is mainly focused on metastatic BC. Therefore, coagulopathies of nonmetastatic BC are understudied and require in-depth investigation. In this study, clot kinetics and ultrastructure were used to investigate treatment-naïve, nonmetastatic BC patients using scanning electron microscopy, Thromboelastography®, and confocal laser scanning microscopy. It was demonstrated that nonmetastatic BC patients exhibit minimal ultrastructural alterations of the clot components and no changes in the clot kinetics. However, BC patients presented changes to fibrinogen protein structure, compared to matched controls, using an amyloid-selective stain. Together, these findings suggest that coagulation dysfunction(s) in BC patients with early disease manifest at the microlevel, rather than the macrolevel. This study presents novel insights to a method that are more sensitive to coagulation changes in this specific patient group, emphasizing that the coagulation system may react in different forms to the disease, depending on the progression of the disease itself.


Assuntos
Neoplasias da Mama , Trombose , Coagulação Sanguínea , Testes de Coagulação Sanguínea , Feminino , Fibrinogênio/análise , Humanos
12.
Curr Med Chem ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33605849

RESUMO

There is a causal relationship between cancer (including colorectal cancer), chronic systemic inflammation and persistent infections, and the presence of dysregulated circulating inflammatory markers. It is known that aberrant clot formation and coagulopathies occur in systemic inflammation. In colorectal cancer, there is close link between gut dysbiosis and an inflammatory profile. In this review we present evidence of the connection between gut dysbiosis, the entry of bacteria into the internal environment and the presence of their highly potent inflammagenic molecules, such as lipopolysaccharide and lipoteichoic acid, in circulation. These bacterial components may act as one of the main drivers of the inflammatory process (including hypercoagulation) in colorectal cancer. We review literature that points to the role of these bacterial inflammagens and how they contribute to colorectal carcinogenesis. Insight into the factors that promote carcinogenesis is crucial to effectively prevent and screen for colorectal cancer. Early diagnosis of an activated coagulation system and the detection of bacterial components in circulation and also in the tumour microenvironment, could therefore be important, and may also, together with modulation of the gut microbiota, serve as potential therapeutic targets.

13.
Int J Mol Sci ; 21(21)2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33153161

RESUMO

Progressive respiratory failure is seen as a major cause of death in severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection. Relatively little is known about the associated morphologic and molecular changes in the circulation of these patients. In particular, platelet and erythrocyte pathology might result in severe vascular issues, and the manifestations may include thrombotic complications. These thrombotic pathologies may be both extrapulmonary and intrapulmonary and may be central to respiratory failure. Previously, we reported the presence of amyloid microclots in the circulation of patients with coronavirus disease 2019 (COVID-19). Here, we investigate the presence of related circulating biomarkers, including C-reactive protein (CRP), serum ferritin, and P-selectin. These biomarkers are well-known to interact with, and cause pathology to, platelets and erythrocytes. We also study the structure of platelets and erythrocytes using fluorescence microscopy (using the markers PAC-1 and CD62PE) and scanning electron microscopy. Thromboelastography and viscometry were also used to study coagulation parameters and plasma viscosity. We conclude that structural pathologies found in platelets and erythrocytes, together with spontaneously formed amyloid microclots, may be central to vascular changes observed during COVID-19 progression, including thrombotic microangiopathy, diffuse intravascular coagulation, and large-vessel thrombosis, as well as ground-glass opacities in the lungs. Consequently, this clinical snapshot of COVID-19 strongly suggests that it is also a true vascular disease and considering it as such should form an essential part of a clinical treatment regime.


Assuntos
Plaquetas/patologia , Doenças Cardiovasculares/virologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Eritrócitos/patologia , Ferritinas/sangue , Selectina-P/sangue , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Betacoronavirus/isolamento & purificação , Coagulação Sanguínea/fisiologia , Plaquetas/virologia , COVID-19 , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/patologia , Infecções por Coronavirus/virologia , Eritrócitos/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , SARS-CoV-2 , Trombose/patologia , Trombose/virologia
14.
Cardiovasc Diabetol ; 19(1): 193, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203441

RESUMO

BACKGROUND: Type 2 Diabetes Mellitus (T2DM) is a well-known comorbidity to COVID-19 and coagulopathies are a common accompaniment to both T2DM and COVID-19. In addition, patients with COVID-19 are known to develop micro-clots within the lungs. The rapid detection of COVID-19 uses genotypic testing for the presence of SARS-Cov-2 virus in nasopharyngeal swabs, but it can have a poor sensitivity. A rapid, host-based physiological test that indicated clotting severity and the extent of clotting pathologies in the individual who was infected or not would be highly desirable. METHODS: Platelet poor plasma (PPP) was collected and frozen. On the day of analysis, PPP samples were thawed and analysed. We show here that microclots can be detected in the native plasma of twenty COVID-19, as well as ten T2DM patients, without the addition of any clotting agent, and in particular that such clots are amyloid in nature as judged by a standard fluorogenic stain. Results were compared to ten healthy age-matched individuals. RESULTS: In COVID-19 plasma these microclots are significantly increased when compared to the levels in T2DM. CONCLUSIONS: This fluorogenic test may provide a rapid and convenient test with 100% sensitivity (P < 0.0001) and is consistent with the recognition that the early detection and prevention of such clotting can have an important role in therapy.


Assuntos
Amiloide/sangue , COVID-19/sangue , Diabetes Mellitus Tipo 2/sangue , SARS-CoV-2 , Trombose/sangue , COVID-19/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Trombose/epidemiologia
15.
Front Immunol ; 11: 1551, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793214

RESUMO

Background: Porphyromonas gingivalis and its inflammagens are associated with a number of systemic diseases, such as cardiovascular disease and type 2 diabetes (T2DM). The proteases, gingipains, have also recently been identified in the brains of Alzheimer's disease patients and in the blood of Parkinson's disease patients. Bacterial inflammagens, including lipopolysaccharides (LPSs) and various proteases in circulation, may drive systemic inflammation. Methods: Here, we investigate the effects of the bacterial products LPS from Escherichia coli and Porphyromonas gingivalis, and also the P. gingivalis gingipain [recombinant P. gingivalis gingipain R1 (RgpA)], on clot architecture and clot formation in whole blood and plasma from healthy individuals, as well as in purified fibrinogen models. Structural analysis of clots was performed using confocal microscopy, scanning electron microscopy, and AFM-Raman imaging. We use thromboelastography® (TEG®) and rheometry to compare the static and dynamic mechanical properties of clots. Results: We found that these inflammagens may interact with fibrin(ogen) and this interaction causes anomalous blood clotting. Conclusions: These techniques, in combination, provide insight into the effects of these bacterial products on cardiovascular health, and particularly clot structure and mechanics.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Cisteína Endopeptidases Gingipaínas/química , Cisteína Endopeptidases Gingipaínas/farmacologia , Fenômenos Mecânicos , Porphyromonas gingivalis/enzimologia , Adulto , Feminino , Fibrina/química , Fibrinogênio/química , Fibrinogênio/ultraestrutura , Humanos , Lipopolissacarídeos/efeitos adversos , Masculino , Microscopia de Força Atômica , Microscopia Confocal , Pessoa de Meia-Idade , Proteínas Recombinantes , Reologia , Análise Espectral Raman , Trombose/tratamento farmacológico , Adulto Jovem
16.
Int J Mol Sci ; 21(14)2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32708334

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), also known as coronavirus disease 2019 (COVID-19)-induced infection, is strongly associated with various coagulopathies that may result in either bleeding and thrombocytopenia or hypercoagulation and thrombosis. Thrombotic and bleeding or thrombotic pathologies are significant accompaniments to acute respiratory syndrome and lung complications in COVID-19. Thrombotic events and bleeding often occur in subjects with weak constitutions, multiple risk factors and comorbidities. Of particular interest are the various circulating inflammatory coagulation biomarkers involved directly in clotting, with specific focus on fibrin(ogen), D-dimer, P-selectin and von Willebrand Factor (VWF). Central to the activity of these biomarkers are their receptors and signalling pathways on endothelial cells, platelets and erythrocytes. In this review, we discuss vascular implications of COVID-19 and relate this to circulating biomarker, endothelial, erythrocyte and platelet dysfunction. During the progression of the disease, these markers may either be within healthy levels, upregulated or eventually depleted. Most significant is that patients need to be treated early in the disease progression, when high levels of VWF, P-selectin and fibrinogen are present, with normal or slightly increased levels of D-dimer (however, D-dimer levels will rapidly increase as the disease progresses). Progression to VWF and fibrinogen depletion with high D-dimer levels and even higher P-selectin levels, followed by the cytokine storm, will be indicative of a poor prognosis. We conclude by looking at point-of-care devices and methodologies in COVID-19 management and suggest that a personalized medicine approach should be considered in the treatment of patients.


Assuntos
Plaquetas/metabolismo , Infecções por Coronavirus/patologia , Células Endoteliais/metabolismo , Eritrócitos/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Selectina-P/metabolismo , Pneumonia Viral/patologia , Fator de von Willebrand/metabolismo , Betacoronavirus , COVID-19 , Síndrome da Liberação de Citocina/patologia , Humanos , Pandemias , Sistemas Automatizados de Assistência Junto ao Leito , Medicina de Precisão/métodos , SARS-CoV-2 , Trombocitopenia/patologia , Trombose/patologia
17.
Eur J Clin Microbiol Infect Dis ; 39(11): 2013-2018, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32564247

RESUMO

Porphyromonas gingivalis, a major subgingival plaque bacterium in periodontitis, has recently attracted much attention as a possible microbial driver in Alzheimer's disease. In the present paper, another common neuroinflammatory disease, Parkinson's disease (PD), is discussed. A recent study found major virulence factors of P. gingivalis such as gingipain R1 (RgpA) and lipopolysaccharide in the blood circulation of a PD population. The current review reveals how features such as systemic inflammation, hypercoagulation, presence of amyloid fibrin(ogen) in plasma, and marked ultrastructural changes in platelets, probably induced by P. gingivalis, may affect the development of PD. Several other clinical studies have also demonstrated an association between periodontitis and PD. Even if the risk of periodontal diseases causing neurological disorders needs to be better substantiated, that should not keep us from trying to prevent them by performing careful daily dental hygiene.


Assuntos
Doença de Parkinson/etiologia , Porphyromonas gingivalis/patogenicidade , Humanos , Fatores de Virulência
18.
Front Immunol ; 11: 1221, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574271

RESUMO

Lactoferrin is a nutrient classically found in mammalian milk. It binds iron and is transferred via a variety of receptors into and between cells, serum, bile, and cerebrospinal fluid. It has important immunological properties, and is both antibacterial and antiviral. In particular, there is evidence that it can bind to at least some of the receptors used by coronaviruses and thereby block their entry. Of importance are Heparan Sulfate Proteoglycans (HSPGs) and the host receptor angiotensin-converting enzyme 2 (ACE2), as based on other activities lactoferrin might prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from attaching to the host cells. Lactoferrin (and more specifically enteric-coated LF because of increased bioavailability) may consequently be of preventive and therapeutic value during the present COVID-19 pandemic.


Assuntos
Proteoglicanas de Heparan Sulfato/metabolismo , Lactoferrina/fisiologia , Lactoferrina/uso terapêutico , Peptidil Dipeptidase A/metabolismo , Receptores Virais/metabolismo , Enzima de Conversão de Angiotensina 2 , Animais , Antibacterianos/uso terapêutico , Infecções Bacterianas/prevenção & controle , Suplementos Nutricionais , Humanos , Lactoferrina/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores de Coronavírus , Viroses/prevenção & controle
19.
Retrovirology ; 17(1): 14, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32571345

RESUMO

BACKGROUND: Patients infected with the human immunodeficiency virus (HIV) are more prone to systemic inflammation and pathological clotting, and many may develop deep vein thrombosis (DVT) as a result of this dysregulated inflammatory profile. Coagulation tests are not routinely performed unless there is a specific reason. METHODS: We recruited ten healthy control subjects, 35 HIV negative patients with deep vein thrombosis (HIV negative-DVT), and 13 HIV patients with DVT (HIV positive-DVT) on the primary antiretroviral therapy (ARV) regimen-emtricitabine, tenofovir and efavirenz. Serum inflammatory markers, haematological results, viscoelastic properties using thromboelastography (TEG) and scanning electron microscopy (SEM) of whole blood (WB) were used to compare the groups. RESULTS: The DVT patients (HIV positive and HIV negative) had raised inflammatory markers. The HIV positive-DVT group had anaemia in keeping with anaemia of chronic disorders. DVT patients had a hypercoagulable profile on the TEG but no significant difference between HIV negative-DVT and HIV positive-DVT groups. The TEG analysis compared well and supported our ultrastructural results. Scanning electron microscopy of DVT patient's red blood cells (RBCs) and platelets demonstrated inflammatory changes including abnormal cell shapes, irregular membranes and microparticle formation. All the ultrastructural changes were more prominent in the HIV positive-DVT patients. CONCLUSIONS: Although there were trends that HIV-positive patients were more hypercoagulable on functional tests (viscoelastic profile) compared to HIV-negative patients, there were no significant differences between the 2 groups. The sample size was, however, small in number. Morphologically there were inflammatory changes in patients with DVT. These ultrastructural changes, specifically with regard to platelets, appear more pronounced in HIV-positive patients which may contribute to increased risk for hypercoagulability and deep vein thrombosis.


Assuntos
Coagulação Sanguínea , Infecções por HIV/sangue , Infecções por HIV/complicações , Trombose Venosa/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Antirretroviral de Alta Atividade , Estudos de Casos e Controles , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Inflamação/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Trombose Venosa/virologia , Adulto Jovem
20.
Sci Rep ; 10(1): 8777, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32472080

RESUMO

Gut dysbiosis contributes to the development of a dysfunctional gut barrier, facilitating the translocation of bacteria and inflammagens, and is implicated in colorectal cancer (CRC) pathogenesis. Such 'leaky gut' conditions result in systemic inflammation, of which a hallmark is increased hypercoagulability. Fluorescence antibody confocal microscopy was used to determine circulating levels of lipopolysaccharide (LPS) in control and CRC populations. Here we showed that circulating levels of LPS are significantly elevated in the CRC population. We also showed that markers of inflammation and hypercoagulability are increased in this population. Furthermore, anomalous blood clotting and structural changes in blood components are presented. Importantly, the association between LPS levels, inflammation, and hematological dysfunction was analysed. Statistical regression models were applied to identify markers with strong association with CRC, and to investigate the correlation between markers. A core aim is enhanced biomarker discovery for CRC. We conclude that circulating LPS can promote systemic inflammation and contribute to the development of a pathological coagulation system, with resulting chronic inflammation and an activated coagulation system implicated in tumorigenesis. Blood-based screening tools are an emerging research area of interest for CRC screening. We propose the use of additional (novel) biomarkers to effectively screen for CRC.


Assuntos
Neoplasias Colorretais/sangue , Disbiose/sangue , Lipopolissacarídeos/sangue , Trombofilia/etiologia , Idoso , Translocação Bacteriana , Células Sanguíneas/ultraestrutura , Disbiose/etiologia , Endotélio Vascular/lesões , Feminino , Microbioma Gastrointestinal , Humanos , Inflamação/sangue , Lipídeos/sangue , Masculino , Microscopia Eletrônica de Varredura , Pessoa de Meia-Idade , Plasma , Tromboelastografia , Trombofilia/sangue
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